Parenteral injection refers to the administration of drugs or vaccines via injection under or through one or more layers of skin or mucus membranes of an animal. Standard injections are given into the subcutaneous or intramuscular region of an animal, e.g., a human patient. These deep locations are targeted because the tissue expands more easily, relative to shallow dermal sites, to accommodate the 0.1-3.0 cc (ml) injection volumes required to deliver most therapeutic agents.
Generally, injections have been classified into different categories, including (1) solutions ready for injection; (2) dry, soluble ready to be combined with a solvent just prior to being injected into a patient; (3) dry, insoluble products ready to be combined with a suitable injection medium prior to administration; (4) suspensions ready for injection; and (5) emulsions ready for injection. Such injectable formulations are administered by routes including intravenous, subcutaneous, intradermal, intramuscular, intraspinal, intrasisternal, and intrathecal. The nature of the therapeutic agent quickly determines the route of administration. On the other hand, the desired route of administration places constraints on the therapeutic formulation itself. For example, solutions for subcutaneous administration require strict attention to tonicity adjustment in order to avoid irritation to the nerves and tissue in the surrounding area of injection. Likewise, suspensions are not administered directly into the blood stream in view of the potential of insoluble particles blocking capillaries.
In comparison to other dosage forms and routes of administration, injectables possess certain advantages, including immediate physiological action (e.g., via intravenous injection), avoidance of intestinal absorption problems attended with many drugs, and the accurate administration of the desired dose into the blood stream of a patient. On the other hand, one of the disadvantages of injectables is the pain and discomfort present at the site of administration associated with certain pharmaceutically active agents, as well as the trauma of having a needle inserted under the skin or into a vein. There is a degree of discomfort for the patient with each injection which is administered.
Currently, biopharmaceutical agents are typically reconstituted into sterile solutions and are administered into the subcutaneous or intramuscular space using a large gauge needle, e.g., in the range 18-30 gauge. Pain is caused by the depth of the penetration of the needle, the size “gauge” of the needle, the large volume of injection, and the diffusion of drug away from the site of injection, among other things. In addition to problems with administration of injectables due to pain associated with the same, there are other draw backs of current practices with respect to injections. For example, many protein and sustained release drugs require reconstitution immediately prior to administration. Dosing of drugs can be inflexible and inaccurate. Further, many formulations need to be refrigerated in order to protect the drugs from degrading hydrolysis reactions. Further, present administration systems are wasteful in that the injection device retains a significant amount of the drug product. Further, to effect delivery of the necessary dose required, an injectable formulation typically must be concentrated and stabilized. Standard injections are given in the liquid form. Products that are sold as liquids or a lyophilized powder require reconstitution in an aqueous carrier prior to injection. Many therapeutic protein and vaccine products are produced in a dry, solid form to promote stability while on the shelf. These formulations are diluted prior to injection in sterile water, phosphate buffer solution, or isotonic saline.
Unlike the subcutaneous and intramuscular regions, the dermal area is shallow with limited expansion. The stratum corneum is relatively thin—only 5 to 15 microns. The dermal area is unable to accommodate injection volumes of greater than 0.5 ml required for most therapeutic injectables. Intradermal injections have been used to date primarily for diagnostic testing to determine exposure to diseases. Certain therapeutic substances (e.g., hepatitis B vaccines) are more effectively absorbed into or react with the immune response system when injected intradermally. Other substances require intradermal administration for diagnostic testing. Intradermal tissues are well supplied with blood vessels and have a rapid rate of absorption of substances injected therein. The absorption rate and limited volume (<0.5 ml) that may be injected intradermally has rendered intradermal injections generally unsatisfactory for therapeutic purposes. The ventral surface of the forearms and the scapular surfaces are the most common used for intradermal injection. Other potential sites include the upper arms and upper chest areas.
Syringes for intradermal injections are known. A typical syringe includes a needle shaft, lumen, bevel, hilt or hub opening, barrel or cartridge which contains liquid medications, tip and a plunger which includes an activation flange at one end and a rubber stopper at an opposite end. The barrel is the outer round part, typically made of glass or plastic. The plunger, typically made of plastic, is the piston-like part that moves up and down inside the barrel. The tip is the small projection that fits inside the hub of the needle. There are two types of tips—plain and locking. A plain tip is tapered to fit tightly inside the hub of the needle and holds the needle in place by friction. A locking tip has a treaded outer collar, which is sized to accept the needle hub. The basic components of the needle are the hub, shaft and bevel. The hub is the enlarged portion at the end of the needle that fits over the tip of the syringe. The shaft is the long slender part, and the bevel is the angled tip of the needle. Syringes for administration of intradermal injection typically are 1 ml (1 cc) tuberculin, between 25-27 gauge, with a ¼ or ½ inch needle, and inject a volume of 0.1 to 0.5 ml maximum for adults. Most intradermal injections are 0.1 ml maximum. Some syringes are prepackaged with needles already attached; others are not. Therefore, the 1 ml syringe may require that the needle be attached to the syringe using aseptic technique. Once the syringe and needle have been assembled the medication is drawn up from a vial or ampule. Vials are single or multidose glass containers, which are sealed with a thick rubber stopper. The stopper or diaphragm is covered with a metal or plastic cap to ensure sterility. The medication in vials is either in the form of a solution or dry sterile powder. If the medication is in powder form, it will have to be reconstituted with the appropriate diluent in the appropriate volume. The proper procedure for drawing a drug from a vial is to remove the protective cap on the vial and clean off the diaphragm with an alcohol swab. The plunger is pulled back to aspirate the needed amount of air and the needle is inserted in the center of the rubber diaphragm. Air is injected and the drug is aspirated. Errors occur if the wrong diluent or the wrong amount of diluent is used. If the medication is in an ampule, the ampule must be opened. A filter (e.g., filter straw) is required to prevent tiny glass particles from being drawn up into the syringe. Failure to use a filter needle may result in patent injury and/or blockage of the needle preventing flow of medication. The filter must be removed and the needle attached to the syringe prior to administration. Errors occur where there is a failure to remove the filter resulting in injection of glass particles. Further, the additional step of attaching and removing the filter from the syringe requires aseptic technique to reduce the risk of nosocomial infections.
There is needed in the art methods and formulations to provide concentrated dosing of therapeutic agents, vaccines, and other biopharmaceuticals in a concentrated dose via intracutaneous injection into the epidermal, dermal or subcutaneous layer of the skin. It is further desirable to provide such formulations in a stabilized platform which does not require reconstitution or refrigeration. It is further desirable to prepare such formulations and administer the same in a manner which substantially avoids pain associated with injection of such agents.